Targeted polyethylene glycol gold nanoparticles for the treatment of pancreatic cancer: from synthesis to proof-of-concept in vitro studies

Abstract

International audienceThe main objective of this study was to optimize and characterize a drug delivery carrier for doxorubicin, intended to be intravenously administered, capable of improving the therapeutic index of the chemotherapeutic agent itself, and aimed at the treatment of pancreatic cancer. In light of this goal, we report a robust one-step method for the synthesis of dicarboxylic acid-terminated polyethylene glycol (PEG)-gold nanoparticles (AuNPs) and doxorubicin-loaded PEG-AuNPs, and their further antibody targeting (anti-Kv11.1 polyclonal antibody [pAb]). In in vitro proof-of-concept studies, we evaluated the influence of the nanocarrier and of the active targeting functionality on the anti-tumor efficacy of doxorubicin, with respect to its half-maximal effective concentration (EC50) and drug-triggered changes in the cell cycle. Our results demonstrated that the therapeutic efficacy of doxorubicin was positively influenced not only by the active targeting exploited through anti-Kv11.1-pAb but also by the drug coupling with a nanometer-sized delivery system, which indeed resulted in a 30-fold decrease of doxorubicin EC50, cell cycle blockage, and drug localization in the cell nuclei. The cell internalization pathway was strongly influenced by the active targeting of the Kv11.1 subunit of the human Ether-à-go-go related gene 1 (hERG1) channel aberrantly expressed on the membrane of pancreatic cancer cells. Targeted PEG-AuNPs were translocated into the lysosomes and were associated to an increased lysosomal function in PANC-1 cells. Additionally, doxorubicin release into an aqueous environment was almost negligible after 7 days, suggesting that drug release from PEG-AuNPs was triggered by enzymatic activity. Although preliminary, data gathered from this study have considerable potential in the application of safe-by-design nano-enabled drug-delivery systems (ie, nanomedicines) for the treatment of pancreatic cancer, a disease with a poor prognosis and one of the main current burdens of today’s health care bill of industrialized countries

HIV‐1 Tat Peptide‐Gemcitabine Gold (III)‐PEGylated Complex—Nanoflowers: A Sleek Thermosensitive Hybrid Nanocarrier as Prospective Anticancer

“…We tested, PANC‐1 to understand the activity of gemcitabine had been retained in the nanoconjugated form. The percentage (%) of live PDAC cells (PANC‐1 cell line) were evaluated by flow cytometry after exposure of 48 h with PEG‐AuNPs as control, GEM ION‐PEG‐AuNPs and HIV‐1 Tat GEM ION‐PEG‐AuNPs. As described previously, PEG‐COOH do not impact on the toxicity of the final nanocarrier .…”

Industrial grade 2D molybdenum disulphide (MoS 2 ): an in vitro exploration of the impact on cellular uptake, cytotoxicity, and inflammation

“…However, before translation into industrial or biomedical arenas, the question of MoS 2 cytotoxicity, uptake and inflammatory response should be addressed to understand the potential health impacts following exposure during material synthesis, device manufacturing, consumer or patient exposure. For biomedical applications , the use of nanomaterials can increase drug delivery, reduce systemic affects and potentially cause confined detrimental effects to abnormal and/or cancerous cells using a targeted nanotherapy (14). Internalisation of nanomaterials can improve drug delivery while improving efficiency, as higher concentrations are delivered within each cell while healthy and/or neighbouring cells are protected.…”

Novel Synthesis and Characterization of Doxycycline‐Loaded Gold Nanoparticles: The Golden Doxycycline for Antibacterial Applications

“…Gold ions are consequently reduced on the surface of gold nuclei, therefore involving the achievement of spherical gold nanoparticles of smaller sizes, which are embedded and stabilized by DOXY ( Schemes A and ). In order to improve the stability and biological activity of the gold nanoparticles in object, we decided to apply some modification to original synthesis, through the methodology ON and IN extensively described by Spadavecchia and co‐workers …”

“…The AuNPs thus formed were characterized by TEM and have spherical shape (Figure B–b) with a diameter close to 23 ± 4.2 nm, confirmed by the hydrodynamic diameter measured by zetasizer (Table S1, Supporting Information). Previously Spadavecchia and co‐workers have reported the synthesis of similar nanostructures using dicarboxylic PEG obtaining PEG AuNPs as building block of nanovectors …”

“…Recently, Spadavecchia and co‐workers have synthesized an original nanovector based on doxorubicin–gold complex, by a chelation reaction in which, the drug was complex with tetrachloauric acid (HAuCl 4 ) and polymer molecules before reduction to final nanovector (DOX IN‐AuNPs) . The same authors have also studied the mechanism of hybrid nanoparticles using doxorubicin capped onto gold nanoparticles with biocompatible polymers as capping agent (DOX ON‐AuNPs) in order to compare the different activity of both nanovectors, and their remarkable interest in therapeutic activity to in vitro model of pancreatic ductal adeno carcinoma …”